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Caspase, a family of cysteine proteases, serve as effectors in apoptosis. The ced3 gene in C.elegans was first identified to be involved in apoptosis. This gene encodes the ced-3 caspase that is similar to the interleukin-1-beta converting enzyme or ICE in mammals. In addition to apoptosis, caspases also function in the inflammatory response. Inflammatory caspases are essential in activating pro-inflammatory cytokines that recruit immune cells and block the replication of pathogens inside...
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For successful DNA replication, the unwinding of double-stranded DNA must be accompanied by stabilization and protection of the separated single strands of the DNA. This crucial task is performed by single-strand DNA-binding (SSB) proteins. They bind to the DNA in a sequence-independent manner, which means that the nitrogenous bases of the DNA need not be present in a specific order for binding of SSB proteins to it. The binding of SSB proteins straightens single-stranded DNA (ssDNA) and makes...
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The native conformation of a protein is formed by interactions between the side chains of its constituent amino acids. When the amino acids cannot form these interactions, the protein cannot fold by itself and needs chaperones. Notably, chaperones do not relay any additional information required for the folding of polypeptides; the native conformation of a protein is determined solely by its amino acid sequence. Chaperones catalyze protein folding without being a part of the folded protein.
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Caspase-6 Undergoes a Distinct Helix-Strand Interconversion upon Substrate Binding.

Kevin B Dagbay1, Nicolas Bolik-Coulon1, Sergey N Savinov2

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|February 4, 2017
PubMed
Summary
This summary is machine-generated.

Caspase-6, crucial in neurodegeneration, exhibits unique conformational flexibility between helical and strand states, unlike caspase-7. This dynamic equilibrium, regulated by Glu-135, is key to its function and potential therapeutic targeting.

Keywords:
apoptosiscysteine proteasehydrogen exchange mass spectrometrymolecular dynamicsneurodegeneration

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Area of Science:

  • Biochemistry
  • Structural Biology
  • Neuroscience

Background:

  • Caspases are proteases involved in apoptosis and inflammation.
  • Caspase-6 plays a critical role in neurodegeneration, but its precise targeting is challenging due to structural similarities with other caspases.
  • Caspase active sites typically adopt a canonical β-strand conformation for substrate binding.

Purpose of the Study:

  • To investigate the conformational dynamics of caspase-6, particularly the interconversion between helical and strand conformations.
  • To understand the unique structural features of caspase-6 that differentiate it from other caspases.
  • To explore the potential for therapeutic targeting of caspase-6 based on its conformational flexibility.

Main Methods:

  • Hydrogen/deuterium exchange mass spectrometry (HDX-MS) was employed to assess conformational dynamics.
  • Comparative analysis of caspase-6 and caspase-7 conformational behavior was performed.
  • Computational analysis of pK values for key residues was conducted.

Main Results:

  • Caspase-6 exhibits significantly greater conformational flexibility than caspase-7.
  • Caspase-6 exists in a dynamic equilibrium between helical and strand conformations before substrate binding.
  • Substrate binding induces a transition of caspase-6 exclusively to the canonical strand conformation.
  • Glu-135 appears critical for the helix-strand conformational interconversion.

Conclusions:

  • Caspase-6 possesses unique conformational dynamics, including a pre-substrate helical conformation, distinguishing it from other caspases.
  • The conformational flexibility of caspase-6 is regulated by specific residues like Glu-135.
  • Understanding these unique structural features and dynamics offers potential therapeutic strategies for neurodegenerative diseases involving caspase-6.